3pgi

Endothiapepsin in complex with a fragment

spinqualitylabelsall models 3pgi, resolution 1.90Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 3pgi is a 1 chain structure with sequence from Cryphonectria parasitica. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: F41, GOL Related: 3pb5, 3pbd, 3pbz, 3pcw, 3pcz, 3pi0, 3pld, 3pm4, 3pmu, 3pmy Activity: Endothiapepsin, with EC number 3.4.23.22 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed Druglike molecules are defined by Lipinski's rule of 5, to characterize fragment thresholds, they have been reduced from 5 to 3 (Astex's rule of 3). They are applied to assemble fragment libraries, and providers use them to select fragments for commercial offer. We question whether these rules are too stringent to compose fragment libraries with candidates exhibiting sufficient room for chemical subsequent growing and merging modifications as appropriate functional groups for chemical transformations are required. Usually these groups exhibit properties as hydrogen bond donors/acceptors and provide entry points for optimization chemistry. We therefore designed a fragment library (364 entries) without strictly applying the rule of 3. For initial screening for endothiapepsin binding, we performed a biochemical cleavage assay of a fluorogenic substrate at 1 mM. "Hits" were defined to inhibit the enzyme by at least 40%. Fifty-five hits were suggested and subsequently soaked into endothiapepsin crystals. Eleven crystal structures could be determined covering fragments with diverse binding modes: (i) direct binding to the catalytic dyad aspartates, (ii) water-mediated binding to the aspartates, (iii) no direct interaction with the dyad. They occupy different specificity pockets. Only 4 of the 11 fragments are consistent with the rule of 3. Restriction to this rule would have limited the fragment hits to a strongly reduced variety of chemotypes. A Small Nonrule of 3 Compatible Fragment Library Provides High Hit Rate of Endothiapepsin Crystal Structures with Various Fragment Chemotypes.,Koster H, Craan T, Brass S, Herhaus C, Zentgraf M, Neumann L, Heine A, Klebe G J Med Chem. 2011 Oct 25. PMID:21972967 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Pepsin

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